title: Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations.
abstract: The pathophysiological concept of ischaemic stroke was recently expanded to a more comprehensive perspective, focussing on the vasculature as well as peri- and juxtavascular cells including astrocytes. Increasing evidence also supports a role of the vasculature in Alzheimer's disease (AD), but causal relationships are poorly understood. The purpose of this study was to examine vascular alterations due to cerebral ischaemia in aged wildtype (WT) mice and in the triple-transgenic (3xTg) mouse model of AD. Three- and 12-month-old WT and 3xTg mice underwent permanent middle cerebral artery occlusion. One day after ischaemia onset, expression of collagen IV and laminin as basement membrane constituents, and Solanum tuberosum lectin (STL) as endothelial marker was quantified in the ischaemic neocortex, striatum and hippocampus. Further, CD31- and aquaporin-4-immunoreactivity served for coverage of endothelium and astrocyte endfeet. Ischaemia resulted in strong upregulation of collagen IV and laminin in the neocortex of 3-month-old WT and 3xTg mice, while STL appeared unaffected. Quantification confirmed collagen IV upregulation in the ischaemic neocortex of 3- and 12-month-old WT and 3xTg mice, whereas striatal changes were limited to young WT mice. However, collagen IV expression in the hippocampus appeared nearly unaltered. Qualitative and quantitative data evidenced more severe degeneration of endothelial cells and astrocyte endfeet in 3xTg mice. In conclusion, this study supports the critical impact of the vasculature in the aged and AD brain by showing an age- and genetic background-dependent response of basement membranes to cerebral ischaemia, and a pronounced endothelial and astrocytic degeneration in the AD-like brain.
authors.affiliation: Clinical and Experimental Sciences, University of Southampton, Tremona Road, Southampton, Hampshire, UK.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.forename: Dominik
authors.initials: D
authors.lastname: Michalski
authors.forename: Rebecca
authors.initials: R
authors.lastname: Anders
authors.forename: Sabine
authors.initials: S
authors.lastname: Nissel
authors.forename: Jens
authors.initials: J
authors.lastname: Grosche
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Roxana O
authors.initials: RO
authors.lastname: Carare
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D024141:Collagen Type IV / Q000032:analysis / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D007797:Laminin / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020521:Stroke / Q000150:complications* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D024141:Collagen Type IV; D007797:Laminin
keywords: Alzheimer's disease; Basement membrane; Endothelium; Ischaemic stroke